Elastase, which is one of the proteolytic enzymes, has been said to play an important role in metabolism of living tissue. In particular, elastase, which is secreted from neutrophils which are one type of lymphocyte, is involved in infectious disease and inflammation of tissue, and may act in protection against infection and regeneration of damaged tissue. A protein having elastase inhibitory activity is also produced in the living body, and it acts to prevent excessive degradation of the living tissue by neutralizing the excess elastase activity [Ann. Rev. Med., 36:207-216, (1985)].
As stated above, the balance between the activity of elastase and that of elastase inhibitory protein is strictly regulated and maintained in the living body. When this balance is disturbed various diseases can result. For example, when elastase activity is enhanced, diseases such as pulmonary emphysema, idiopathic pulmonary fibroma, and adult respiratory distress syndrome (ARDS) are caused in the lung [Metabolism, 29:41-49, (1992)], and an increase of neutrophil elastase activity in the joints is thought to be involved in generation of diseases such as rheumatoid arthritis and deformative arthritis [Agents Actions, 8:11-18 (1978); Bulletin of Pharmacological Society of Japan, 99:93-107 (1992)]. Further, elastase is thought to be involved in generation of acute and chronic inflammatory diseases [Ann. Rev. Med., 36:207-216 (1985)].
.alpha. 1-anti-trypsin (hereinafter referred to as ".alpha. 1-AT") has been well known as one of the elastase inhibitory proteins which modulate the activity of elastase in the living body. .alpha. 1-AT exists in blood in a large amount and plays a role in inhibiting and neutralizing elastase activity [Nature, 298:329-334 (1982)]. However, since .alpha. 1-AT is very susceptible to oxidization, when air containing high levels of peroxide owing to smoking and air pollution is inhaled continuously, .alpha. 1-AT is oxidized by the inhaled peroxide in the lung, and the elastase inhibitory activity thereof may be lost [Am. Rev. Respir. Dis., 116:65-72 (1977)].
Further, .alpha. 1-AT is oxidized by oxygen released from leukocytes which migrate to the portion in the lung inflamed by the inhalation of the polluted air containing inflammable materials, and it loses elastase inhibitory activity [J. Clin. Invest., 66:987-995 (1980)]. Such inactivation of .alpha. 1-AT leads to a condition of an excess elastase activity in the limited portion in the lung, then the alveolus tissue is degraded by the excess elastase, and results in lung diseases such as pulmonary emphysema [Area of Chemical Therapy, 5:1455-1459 (1989)]. When bacteria infect the lung, and inflammation is therefore caused at the limited portion in the lung, .alpha. 1-AT is also inactivated and the lung tissue may be destroyed because leukocytes such as neutrophil migrate to the inflammatory site by the infection and they secrete a large amount of active oxygen and elastase [Metabolism, 29:41-49 (1992)].
In order to prevent and treat the diseases involving an elastase aforementioned, it has been said that administration of an elastase inhibitory substance such as .alpha. 1-AT into blood or tissue changed pathologically may be effective [Can. Med. Assoc. J., 146:841-844 (1992)]. However, it is necessary to use the .alpha. 1-AT derived from human to avoid an antigen-antibody reaction as a side-effect. Therefore obtaining enough .alpha. 1-AT for prevention and treatment has been difficult.
In addition, since pathogenic virus derived from human may remain in the purified .alpha. 1-AT products, when an elastase inhibitory substance such as.alpha. 1-AT is extracted and purified from human blood, this is a factor that has presented difficulties in using .alpha. 1-AT derived from human for prevention and treatment of diseases induced by elastase.
Further, although a spray-inhalation method by nebulizer is used commonly for administrating the drugs against lung diseases, since .alpha. 1-AT is very susceptible to oxidization as stated above, elastase inhibitory activity is inactivated by oxidation with the spray and, if administration is performed by another route, is also inactivated with active oxygen generated from various cells in the living body.
Furthermore, application of chemically synthesized low molecular weight elastase inhibitors to the above-referenced diseases has also been studied. However, since substances to be administrated in these methods are foreign substances to the living body, when these are administrated into the living body, undesirable side-effects, such as toxicity, may result. Then, these chemically synthesized low molecular weight elastase inhibitors may also inhibit an activity of the other proteolytic enzymes having important physiological activities, and this lack of specificity restricts the usage of these chemically synthesized low molecular weight elastase inhibitors as drugs of choice against the diseases induced by elastase.
Though elastase inhibitor is thought to be quite useful for preventing and curing the diseases induced by elastase, such as pulmonary emphysema, there are various problems discussed above for the pharmaceutical application of inhibitors derived from human such as .alpha. 1-AT and chemically synthesized low molecular weight elastase inhibitors, and clinical application thereof as a medicine has therefore yet to be accomplished.